Renal and nephrology services (kidneys)

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Research outputs from the Exeter Kidney Unit (Renal services) at the RD&E.

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    Psychological Health in Young Adults With Kidney Failure: A 5-Year Follow-up of the SPEAK Study
    (elsevier, 2023-06-01) Al-Talib, M.; Caskey, F. J.; Inward, C.; Ben-Shlomo, Y.; Hamilton, A. J.
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    COVID-19 Vaccination and New Onset Glomerular Disease: Results from the IRocGN2 International Registry
    (Unknown, 2023-03-01) Waldman, M.; Sinaii, N.; Lerma, E. V.; Kurien, A. A.; Jhaveri, K. D.; Uppal, N. N.; Wanchoo, R.; Avasare, R.; Zuckerman, J. E.; Liew, A.; Gallan, A. J.; El-Meanawy, A.; Yagil, Y.; Lebedev, L.; Baskaran, K.; Vilayur, E.; Cohen, A.; Weerasinghe, N.; Petrakis, I.; Stylianou, K.; Gakiopoulou, H.; Hamilton, A. J.; Edney, N.; Millner, R.; Marinaki, S.; Rein, J. L.; Killen, J. P.; Rodríguez Chagolla, J. M.; Bassil, C.; Lopez Del Valle, R.; Evans, J.; Urisman, A.; Zawaideh, M.; Baxi, P. V.; Rodby, R.; Vankalakunti, M.; Mejia Vilet, J. M.; Ramirez Andrade, S. E.; Homan, M. P.; Vásquez Jiménez, E.; Perinpanayagam, N.; Velez, J. C. Q.; Mohamed, M. M. B.; Mohammed, K. M. G.; Sekar, A.; Ollila, L.; Aron, A. W.; Arellano Arteaga, K. J.; Islam, M.; Berrio, E. M.; Maoujoud, O.; Morales, R. R.; Seipp, R.; Schulze, C. E.; Yenchek, R. H.; Vancea, I.; Muneeb, M.; Howard, L.; Caza, T. N.
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    Development of a competency framework for the Assistant Wellbeing Practitioner (Renal) role
    (Wiley, 2022-12-03) Farrand, P.; Hamilton, A.; Strickland, S.
    BACKGROUND: Many people with kidney disease experience comorbid mental health difficulties that result in worse physical health outcomes alongside greater personal, treatment and societal costs. PROBLEM: Workforce expansion to treat comorbid mental health difficulties has focussed on psychological practitioners. This fails to capitalise on benefits arising from embedding roles to address biopsychosocial outcomes directly within the renal specialty. A competency framework to inform development and training for such a role has not been developed. METHODS: Five-phase process to develop a competency framework for an Assistant Wellbeing Practitioner (Renal) role. Following identification of competency frameworks for roles in psychological practice, health and social care, relevant competencies were synthesised to create a draft competency framework. This framework was revised through consultation events with professionals associated with the renal specialty and Kidney Patient Involvement Network with the framework informing a competency map. RESULTS: The competency map comprised three categories-Knowledge, Values and Principles, Core Skills and Meta-Competencies with specific competencies for an assistant practitioner role to work within the renal specialty identified. Core knowledge and skills included awareness of kidney treatments and common psychosocial difficulties, collaborative care and supporting evidence-based prevention approaches. CONCLUSIONS: Competencies associated with the Assistant Wellbeing Practitioner (Renal) role have the potential to promote mental wellbeing, better physical health and generate social and economic benefits. The competency map can inform training and role evaluation, although addressing implementation issues associated with commissioning physical and mental healthcare is required.
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    Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT
    (NIHR Journals Library, 2022-09-01) Jayne, D.; Walsh, M.; Merkel, P. A.; Peh, C. A.; Szpirt, W.; Puéchal, X.; Fujimoto, S.; Hawley, C.; Khalidi, N.; Jones, R.; Flossmann, O.; Wald, R.; Girard, L.; Levin, A.; Gregorini, G.; Harper, L.; Clark, W.; Pagnoux, C.; Specks, U.; Smyth, L.; Ito-Ihara, T.; de Zoysa, J.; Brezina, B.; Mazzetti, A.; McAlear, C. A.; Reidlinger, D.; Mehta, S.; Ives, N.; Brettell, E. A.; Jarrett, H.; Wheatley, K.; Broadhurst, E.; Casian, A.; Pusey, C. D.
    BACKGROUND: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m(2) or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information. Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a ‘reduced’ or ‘standard’ steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a ‘standard’-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future. eng
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    Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis
    (Cell Press, 2022-08-04) Lemoine, H.; Raud, L.; Foulquier, F.; Sayer, J. A.; Lambert, B.; Olinger, E.; Lefèvre, S.; Knebelmann, B.; Harris, P. C.; Trouvé, P.; Desprès, A.; Duneau, G.; Matignon, M.; Poyet, A.; Jourde-Chiche, N.; Guerrot, D.; Lemoine, S.; Seret, G.; Barroso-Gil, M.; Bingham, C.; Gilbert, R.; Le Meur, Y.; Audrézet, M. P.; Cornec-Le Gall, E.
    Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.